Rheumatoid Arthritis (RA) is a chronic, systemic inflammatory disorder of unknown etiology that predominantly affects synovial joints. RA is, moreover, an autoimmune disease that affects about 1% of the Caucasian population, with a higher ratio of females afflicted (Lee et al. 2001; Lancet 358:903-911). The disease can occur at any age, but it is most common in human subjects between 30 to 55 years old (Sweeney et al. 2004; Int. J. Biochem. Cell Biol. 36:372-378). The incidence of RA increases with age.
Although the cause of RA is unknown, certain genetic and infectious factors have been implicated in RA pathogenesis (Smith et al. 2002; Ann. Intern. Med. 136:908-922). Soluble cytokines and chemokines, such as IL-1β, TNFα, IL-1ra, IL-6, IL-8, MCP-1 and serum amyloid A (SAA), have been shown to be associated with rheumatoid arthritis (Szekanecz et al. 2001; Curr. Rheumatol. Rep. 3:53-63; Gabay et al. 1997; J. Rheumatol. 24:303-308; Arvidson et al. 1994; Ann. Rheum. Dis. 53:521-524; De Benedetti et al. 1999; J. Rheumatol. 26:425-431.
The predominant symptoms of RA are pain, stiffness, and swelling of peripheral joints. Of the synovial joints, RA most commonly affects the joints of the hands, feet and knees (Smolen et al. 1995; Arthritis Rheum. 38:38-43). RA can also, however, affect the spine with devastating results and atlanto-axial joint involvement is common in more progressed disease. Extra-articular involvement is a hallmark of RA, which can range from rheumatoid nodules to life-threatening vasculitis (Smolen et al. 2003; Nat. Rev. Drug Discov. 2:473-488). The disease manifests with variable outcome, ranging from mild, self-limiting arthritis to rapidly progressive multi-system inflammation, which is associated with pronounced morbidity and mortality (Lee et al. 2001; ibid; Sweeney et al 2004; ibid). Joint damage occurs early in the course of the disease as evidenced by the fact that bony erosions are detected in 30 percent of patients at the time of diagnosis (van der Heijde 1985; Br. J. Rheumatol. 34 (Suppl 2): 74-78).
Seven diagnostic criteria recognized by The American Rheumatism Association (ARA) (Arnett et al. 1988; Arthritis Rheum. 31:315-324) are used to diagnose RA. The ARA criteria include: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the hand joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) elevated levels of serum rheumatoid factor (RF); and 7) radiographic changes in hand and/or wrist joints. For a definitive diagnosis of RA, the first four criteria must be present for a minimum of six weeks. The RA test measures rheumatoid factor—the IgM autoantibody reactive with Fc region epitopes of the IgG molecule (Corper et al. 1997; Nat. Struct. Biol. 4: 374-381). Although RF is primarily associated with RA, these antibodies can be detected in sera from normal elderly people, healthy individuals, and patients with other autoimmune disorders or chronic infections (Williams 1998) and thus, have low disease specificity.
RA is typically treated with a variety of drugs that can be categorized as follows: nonsteroidal anti-inflammatory drugs (NSAIDs); disease-modifying anti-rheumatic drugs (DMARDs), steroids, and analgesics. NSAID drugs (such as ibuprofen and aspirin) reduce swelling and pain associated with the disease but offer only symptomatic relief. DMARDs include sulfasalazine and methotrexate, as well as biological agents, such as Infliximab, Etanercept, Adalimumab and Anakinra. All of the above therapeutics, however, fail to address the underlying cause of RA.
In view of the above, new methods for use in the accurate diagnosis, prognosis, and/or monitoring of patients with rheumatoid arthritis are urgently needed. Methods described herein address these needs.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.